Abstract
Colorectal cancer includes an invasive stem-like/mesenchymal subtype, but its genetic drivers, functional, and clinical relevance are uncharacterized. Here we report the definition of an altered miRNA signature defining this subtype that includes a major genomic loss of miR-508. Mechanistic investigations showed that this miRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, and BMI1. Loss of miR-508 in colorectal cancer was associated with upregulation of the novel hypoxia-induced long noncoding RNA AK000053. Ectopic expression of miR-508 in colorectal cancer cells blunted epithelial-to-mesenchymal transition (EMT), stemness, migration, and invasive capacity in vitro and in vivo In clinical colorectal cancer specimens, expression of miR-508 negatively correlated with stemness and EMT-associated gene expression and positively correlated with patient survival. Overall, our results showed that miR-508 is a key functional determinant of the stem-like/mesenchymal colorectal cancer subtype and a candidate therapeutic target for its treatment.Significance: These results define a key functional determinant of a stem-like/mesenchymal subtype of colorectal cancers and a candidate therapeutic target for its treatment. Cancer Res; 78(7); 1751-65. ©2018 AACR.
Highlights
Epithelial-to-mesenchymal transition (EMT) contributes to cancer progression, tumor cell invasion and metastasis, which enables cancer cells to escape the primary tumor mass and colonize new terrain in the body [1]
We found that a novel long noncoding RNA AK000053 was induced by hypoxia via hypoxia inducing factor alpha (HIF-1a), which mechanistically and pathologically contributed to the miR-508 loss in colorectal cancer
On the basis of 198 miRNA-sequence data analyses from the The Cancer Genome Atlas (TCGA) repository, we identified that four miRNAs, miR-506, miR-508, miR-509, and miR-514, were downregulated by more than 2-fold, with an false discovery rate (FDR) < 0.0015 in the stem-like/mesenchymal subtype colorectal cancers compared with other subtypes (Fig. 1C; Supplementary Table S3)
Summary
Epithelial-to-mesenchymal transition (EMT) contributes to cancer progression, tumor cell invasion and metastasis, which enables cancer cells to escape the primary tumor mass and colonize new terrain in the body [1]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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